- Bistacrine derivatives as new potent antimalarials
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Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure–activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.
- Schmidt, Ines,Pradel, Gabriele,Sologub, Ludmilla,Golzmann, Alexandra,Ngwa, Che J.,Kucharski, Anna,Schirmeister, Tanja,Holzgrabe, Ulrike
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- Novel tacrine platinum(II) complexes display high anticancer activity via inhibition of telomerase activity, dysfunction of mitochondria, and activation of the p53 signaling pathway
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In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]?CH3OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4′-dimethyl-2,2′-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1–Pt7 exhibited cytotoxic activity against the tested NCI–H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1–Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug.
- Qin, Qi-Pin,Wang, Shu-Long,Tan, Ming-Xiong,Wang, Zhen-Feng,Luo, Dong-Mei,Zou, Bi-Qun,Liu, Yan-Cheng,Yao, Peng-Fei,Liang, Hong
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- Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimers disease
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A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimers disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.
- Mao, Fei,Li, Jianheng,Wei, Hui,Huang, Ling,Li, Xingshu
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- Convenient synthesis of disubstituted tacrine derivatives via electrophilic and copper induced reactions
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The bromination of 2-aminobenzonitrile (2) with molecular bromine (2?equiv) furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for dibromotacrine derivatives (6, 14–18) utilizing Friedl?nder reactions. A convenient route is described for disubstituted derivatives of tacrines from dibromotacrine 6 and 15 by various substitution reactions. Several disubstituted tacrines were synthesized by treatment of dibromo 6 and 15 derivatives with n-BuLi followed by trapping with an electrophile [Si(Me)3Cl, S2(Me)2]. Both were converted to the corresponding cyano derivatives (21–23) via copper-assisted nucleophilic substitution reactions in moderate yields (30%, 50%, and 60%, respectively). Copper-induced nucleophilic substitution of dibromide 15 with NaOMe afforded mono methoxide 31 in 25% yield.
- Ekiz, Makbule,Tutar, Ahmet,?kten, Salih
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- Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity
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Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 μM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 μM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.
- Kaur Gulati, Harmandeep,Choudhary, Sushil,Kumar, Nitish,Ahmed, Ajaz,Bhagat, Kavita,Vir Singh, Jatinder,Singh, Atamjit,Kumar, Ajay,Singh Bedi, Preet Mohinder,Singh, Harbinder,Mukherjee, Debaraj
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- Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors
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We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M1/M4-preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M1 mAChRs by exploring the interaction of Gαq-PLC-β3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M1 mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.
- Cirillo, Davide,Dallanoce, Clelia,De Amici, Marco,Holzgrabe, Ulrike,Maspero, Marco,Messerer, Regina,Sotriffer, Christoph,Volpato, Daniela,Yuan Chen, Natalia
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- RETRACTED ARTICLE: Sanger's Reagent Sensitized Photocleavage of Amide Bond for Constructing Photocages and Regulation of Biological Functions
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Photolabile groups offer promising tools to study biological processes with high spatial and temporal control. In the investigation, we designed and prepared several new glycine amide derivatives of Sanger's reagent and demonstrated that they serve as a new class of photocages for Zn2+ and an acetylcholinesterase (AChE) inhibitor. We showed that the mechanism for photocleavage of these substances involves initial light-driven cyclization between the 2,4-dinitrophenyl and glycine methylene groups to form acyl benzimidazole N-oxides, which undergo secondary photoinduced decarboxylation in association with rupture of an amide bond. The cleavage reactions proceed with modest to high quantum yields. We demonstrated that these derivatives can be used in targeted intracellular delivery of Zn2+, fluorescent imaging by light-triggered Zn2+ release, and regulation of biological processes including the enzymatic activity of carbonic anhydrase (CA), negative regulation of N-methyl-d-aspartate receptors (NMDARs), and pulse rate of cardiomyocytes. The successful proof-of-concept examples described above open a new avenue for using Sanger's reagent-based glycine amides as photocages for the exploration of complex cellular functions and signaling pathways.
- Wei, Tingwen,Lu, Sheng,Sun, Jiahui,Xu, Zhijun,Yang, Xiao,Wang, Fang,Ma, Yang,Shi, Yun Stone,Chen, Xiaoqiang
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p. 3806 - 3813
(2020/03/10)
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- Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives
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A series of novel tacrine-isatin Schiff base hybrid derivatives (7a-p)were designed, synthesized and evaluated as multi-target candidates against Alzheimer's disease (AD). The biological assays indicated that most of these compounds displayed potent inhibitory activity toward acetylcholinesterase (AChE)and butyrylcholinesterase (BuChE)and specific selectivity for AChE over BuChE. It was also found that they act as excellent metal chelators. The compounds 7k and 7m were found to be good inhibitors of AChE-induced amyloid-beta (Aβ)aggregation. Most of the compounds inhibited AChE with the IC50 values, ranging from 0.42 nM to 79.66 nM. Amongst them, 7k, 7m and 7p, all with a 6 carbon linker between tacrine and isatin Schiff base exhibited the strongest inhibitory activity against AChE with IC50 values of 0.42 nM, 0.62 nM and 0.95 nM, respectively. They were 92-, 62- and 41-fold more active than tacrine (IC50 = 38.72 nM)toward AChE. Most of the compounds also showed a potent BuChE inhibition among which 7d with an IC50 value of 0.11 nM for BuChE is the most potent one (56-fold more potent than that of tacrine (IC50 = 6.21 nM)). In addition, most compounds exhibited the highest metal chelating property. Kinetic and molecular modeling studies revealed that 7k is a mixed-type inhibitor, capable of binding to catalytic and peripheral site of AChE. Our findings make this hybrid scaffold an excellent candidate to modify current drugs in treating Alzheimer's disease (AD).
- Riazimontazer,Sadeghpour,Nadri,Sakhteman,Tüylü Kü?ükk?l?n?,Miri,Edraki
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- Tacrine-Hydrogen Sulfide Donor Hybrid Ameliorates Cognitive Impairment in the Aluminum Chloride Mouse Model of Alzheimer's Disease
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Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by progressive loss of memory and cognitive function, and is associated with the deficiency of synaptic acetylcholine, as well as chronic neuroinflmmation. Tacrine, a potent acetylcholinesterase (AChE) inhibitor, was previously a prescribed clinical therapeutic agent for AD, but it was recently withdrawn because it caused widespread hepatotoxicity. Hydrogen sulfide (H2S) has neuroprotective, hepatoprotective, and anti-inflammatory effects. In this study, we synthesized a new compound, a tacrine-H2S donor hybrid (THS) by introducing H2S-releasing moieties (ACS81) to tacrine. Subsequently, pharmacological and biological evaluations of THS were conducted in the aluminum trichloride (AlCl3)-induced AD mice model. We found that THS (15 mmol/kg) improved cognitive and locomotor activity in AD mice in the step-through test and open field test, respectively. THS showed strong AChE inhibitory activity in the serum and hippocampus of AD mice and induced increased hippocampal H2S levels. Furthermore, THS reduced mRNA expression of the proinflammatory cytokines, TNF-α, IL-6, and IL-1β and increased synapse-associated proteins (synaptophysin and postsynaptic density protein 95) in the hippocampus of AD mice. Importantly, THS, unlike tacrine, did not increase liver transaminases (alanine transaminase and aspartate transaminase) or proinflammatory cytokines, indicating THS is much safer than tacrine. Therefore, the multifunctional effects of this new hybrid compound of tacrine and H2S indicate it is a promising compound for further research into the treatment of AD.
- Cheng, Xiao-Jing,Gu, Jing-Xue,Pang, Yi-Peng,Liu, Jiao,Xu, Ting,Li, Xin-Rui,Hua, Yu-Zhou,Newell, Kelly A.,Huang, Xu-Feng,Yu, Yinghua,Liu, Yi
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p. 3500 - 3509
(2019/07/04)
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- Copper(ii)-catalyzed c-n coupling of aryl halides and n-nucleophiles promoted by quebrachitol or diethylene glycol
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Herein, we report the natural ligand quebrachitol (QCT) as a promoter for a Cu(II) catalyst, which is highly effective for N-Arylation of various amines and related aryl halides. A series of diarylamine derivatives were obtained in high yields by using diethylene glycol (DEG) as both ligand and solvent. The C-N coupling reactions proceed under mild conditions and exhibit good functional group tolerance.
- Chen, Guoliang,Chen, Yuanguang,Du, Fangyu,Fu, Yang,Wu, Ying,Zhou, Qifan
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supporting information
p. 2161 - 2168
(2019/11/25)
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- Tacrine, trolox and tryptoline as lead compounds for the design and synthesis of multi-target agents for alzheimer’s disease therapy
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The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer’s disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety (8a-8d) showed moderate to high TcAChE inhibition (IC50: 17.37 - 2200 nM), eqBuChE inhibition (IC50: 3.16-128.82 nM) and free radical scavenging activities (IC50: 11.48-49.23 μM). The hybrids with longer linker chain lengths in general showed better ChE inhibitory activity. As expected, free radical scavenging activities were not significantly affected by varying linker chain lengths. The hybrid compound containing the tryptoline moiety linked with a 7 carbon spacer to tacrine (14) displayed the best AChE and BuChE inhibitory activity (IC50 = 17.37 and 3.16 nM). Docking experiments exhibited that compounds 8d and 14 were able to bind to both the CAS and PAS of TcAChE and eqBuChE, suggesting that they will be able to inhibit ChE induced Aβ aggregation. Novel multi-target agents that exhibit good ChE inhibition (8d and 14) and anti-oxidant (8d) activity were identified as suitable candidates for further investigation.
- Teponnou, Gerard A. K.,Joubert, Jacques,Malan, Sarel F.
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- Design, synthesis and evaluation of novel tacrine-ferulic acid hybrids as multifunctional drug candidates against Alzheimer's disease
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Five novel tacrine-ferulic acid hybrid compounds (8a-e) were synthesized and their structures were identified on the basis of a detailed spectroscopic analysis. The activities of inhibiting acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE), reducing self-induced β-Amyloid (Aβ) aggregation and chelating Cu2+ were evaluated in vitro. Among them, 8c and 8d displayed the higher selectivity in inhibiting AChE over BuChE. Moreover, 8d also showed dramatic inhibition of self-Aβ aggregation, activity of chelating Cu2+ and activity against Aβ-induced neurotoxicity in Neuro-2A cells.
- Fu, Yingbo,Mu, Yu,Lei, Hui,Wang, Pu,Li, Xin,Leng, Qiao,Han, Li,Qu, Xiaodan,Wang, Zhanyou,Huang, Xueshi
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- Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease
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A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aβ aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity.
- Zhang, Chao,Du, Qiao-Yi,Chen, Lang-Di,Wu, Wen-Hao,Liao, Si-Yan,Yu, Li-Hong,Liang, Xin-Tong
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supporting information
p. 200 - 209
(2016/04/19)
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- Optical control of acetylcholinesterase with a tacrine switch
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Photochromic ligands have been used to control a variety of biological functions, especially in neural systems. Recently, much effort has been invested in the photocontrol of ion channels and G-protein coupled receptors found in the synapse. Herein, we describe the expansion of our photopharmacological approach toward the remote control of an enzyme. Building on hallmark studies dating from the late 1960s, we evaluated photochromic inhibitors of one of the most important enzymes in synaptic transmission, acetylcholinesterase (AChE). Using structure-based design, we synthesized several azobenzene analogues of the well-known AChE inhibitor tacrine (THA) and determined their effects on enzymatic activity. One of our compounds, AzoTHA, is a reversible photochromic blocker of AChE in vitro and ex vivo with high affinity and fast kinetics. As such, AzoTHA can be used to control synaptic transmission on the neuromuscular endplate based on the light-dependent clearance of a neurotransmitter.
- Broichhagen, Johannes,Jurastow, Innokentij,Iwan, Katharina,Kummer, Wolfgang,Trauner, Dirk
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supporting information
p. 7657 - 7660
(2014/08/05)
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- Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease
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A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced β-amyloid (Aβ) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 μM) and Aβ aggregation (67.8%, 20 μM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 μM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment.
- Xie, Sai-Sai,Wang, Xiao-Bing,Li, Jiang-Yan,Yang, Lei,Kong, Ling-Yi
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p. 540 - 553
(2013/07/27)
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- Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine-Homoisoflavonoid hybrids
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A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD).
- Sun, Yang,Chen, Jianwen,Chen, Xuemin,Huang, Ling,Li, Xingshu
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p. 7406 - 7417
(2013/11/19)
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- A concise construction of polycyclic quinolines via annulation of ω-cyano-1-alkynes with diaryliodonium salts
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A concise construction of polycyclic quinolines via intramolecular [2 + 2 + 2] annulation of ω-cyano-1-alkynes with diaryliodonium salts was realized. The process produced polycyclic quinolines in high yields with readily available staring materials and was tolerated with halogen substituents.
- Wang, Yong,Chen, Chao,Zhang, Shu,Lou, Zhenbang,Su, Xiang,Wen, Lirong,Li, Ming
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supporting information
p. 4794 - 4797
(2013/10/08)
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- The divergent transformations of aromatic o-aminonitrile with carbonyl compound
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A modified Friedlaender conversion of the cyclocondensation of aromatic o-aminonitriles with carbonyl compounds was discovered. Systematic studies reveal that both the new transformation and the classic Friedlaender annulation in the presence of ZnCl2 constitute a pair of divergent reaction, and thecontrolled PDF transformation of this divergent reaction was achieved in the present of bases.
- Tang, Jianhong,Li, Jiarong,Zhang, Lijun,Ma, Shuling,Shi, Daxin,Zhang, Qi,Yang, Liupan,Wang, Xiuzhen,Liu, Xuan,Liu, Change
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experimental part
p. 533 - 542
(2012/08/27)
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- Sulfuric acid-modified PEG-6000 (PEG-OSO3H): An efficient, bio-degradable and reusable polymeric catalyst for the solvent-free synthesis of poly-substituted quinolines under microwave irradiation
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Sulfuric acid-modified polyethylene glycol 6000 (PEG-OSO3H) is applied as an efficient and eco-friendly polymeric catalyst for Friedlaender synthesis of poly-substituted quinolines from 2-aminoaryl ketones (or anthranilonitrile) and carbonyl compounds possessing a reactive methylene group under microwave irradiation and solvent-free conditions. The reactions are completed in short times, and the products are obtained in good to excellent yields. The Royal Society of Chemistry.
- Hasaninejad, Alireza,Zare, Abdolkarim,Shekouhy, Mohsen,Ameri-Rad, Javad
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experimental part
p. 958 - 964
(2011/05/12)
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- Design, synthesis and evaluation of tacrine based acetylcholinesterase inhibitors
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A series of tacrine based cholinesterase inhibitors was designed, synthesized and assayed for their biological activity. Among them, five compounds inhibited acetylcholinesterase in micromolar range and most of the compounds demonstrated much better selectivity for AChE than reference compound tacrine.
- Shen, Yanhong,Yu, Youzhu,Lv, Huichao,Feng, Liping,Zhang, Guoqiang
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experimental part
p. 341 - 345
(2011/10/18)
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- Microwave-assisted synthesis of 4-quinolylhydrazines followed by nickel boride reduction: a convenient approach to 4-aminoquinolines and derivatives
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Nickel(II) chloride/sodium borohydride combination was employed for the reduction of 4-hydrazinoquinoline derivatives to the corresponding anilines. This reductive protocol was efficiently applied for the reductive cleavage of monosubstituted hydrazines. We described herein the microwave-assisted synthesis of 4-hydrazinoquinolines, which furnished a high yielding and rapid two-step procedure for the synthesis, under mild conditions, of 4-aminoquinolines as antimalarial precursors.
- Gemma, Sandra,Kukreja, Gagan,Tripaldi, Pierangela,Altarelli, Maria,Bernetti, Matteo,Franceschini, Silvia,Savini, Luisa,Campiani, Giuseppe,Fattorusso, Caterina,Butini, Stefania
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p. 2074 - 2077
(2008/09/18)
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- Synthesis of tacrine derivatives under solventless conditions
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(Chemical Equation Presented) Effects of microwave irradiation on the solid-phase synthesis of tacrine and its derivatives have been evaluated. Preparation of tacrine analogues under conventional conditions suffers from poor synthetic efficiency and usually gives low yield. Reaction of substituted anthranilonitrile with cyclohexanone under microwave irradiation gave a good to excellent yield of the corresponding substituted 9-amino-1,2,3,4- tetrahydroacridines.
- Khalilzadeh, Mohammad A.,Hosseini, Abolfazl,Tajbakhsh', Mahmoud
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p. 535 - 538
(2008/09/16)
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- Convenient preparation of tacrine derivatives by the reduction of 9-aminoacridines with nickel-aluminum alloy
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9-Amino-1,2,3,4-tetrahydro- and 9-amino-1,2,3,4,5,6,7,8-octahydro-acridine derivatives (2 and 3) were conveniently prepared in the reduction of the corresponding 2-substituted 9-aminoacridines (1a-f) with nickel-aluminum alloy under basic conditions. The reduction is dependent upon the nature of the substituent in the 2-position of the starting 9-aminoacridines.
- Kamata, Kichinosuke,Tominaga, Yoh-Ichi,Tori-I, Akiyoshi,Thiemann, Thies,Takahashi, Kazufumi,Mataka, Shuntaro
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p. 1683 - 1688
(2007/10/03)
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- Novel tacrine analogues for potential use against Alzheimer's disease: Potent and selective acetylcholinesterase inhibitors and 5-HT uptake inhibitors
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Several novel analogues of tactine have been synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase, and neuronal uptake of 5-HT (serotonin) and noradrenaline. Changes in the size of the carbocyclic ring of tactine produced modest potency against cholinesterase enzymes. Addition of a fourth ring resulted in compounds with marked selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase [BChE): e.g. 6-amino-4,5-benzo-5H-cyclopenta[1,2-b]-quinoline (14a) had an IC50 of 0.35μM against AChE and 3.1 μM against BChE. Some tetracyclic compounds are 100-400 times more active than tacrine as inhibitors of neuronal uptake of serotonin, in particular 13-amino-6,7-dihydro-5H- benzo[3,4]cyclohepta[1,2-b]quinoline (18), which had an IC50 of 20 nM. These compounds would be expected to facilitate both cholinergic and monoaminergic transmission. They should be worth investigating in models of memory impairment.
- McKenna, Maureen T.,Proctor, George R.,Young, Louise C.,Harvey, Alan L.
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p. 3516 - 3523
(2007/10/03)
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- Method for the preparation of 9-amino-1,2,3,4-tetrahydroacridine
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A method of preparing 9-amino-1,2,3,4-tetrahydroacridine by the reaction of 2-aminobenzonitrile and cyclohexanone with p-toluenesulfonic acid monohydrate in xylenes is disclosed.
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- Method of reducing a carbonyl containing acridine
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A method of reducing a carbonyl containing acridine of the formula STR1 where n is 1, 2 or 3; X is hydrogen, loweralkyl, loweralkoxy, halogen, hydroxy, trifluoromethyl, or NR3 R4 where R3 and R4 are independently hydrogen or loweralkyl; R is hydrogen or loweralkyl and R1 is hydrogen, loweralkyl, diloweralkylaminoloweralkyl, arylloweralkyl, diarylloweralkyl, furylloweralkyl, thienylloweralkyl, oxygen-bridged arylloweralkyl, oxygen-bridged diarylloweralkyl, oxygen-bridged furylloweralkyl or oxygen-bridged thienylloweralkyl, is disclosed.
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- Selective Hydrogenation of 9-Aminoacridine over Supported Noble Metal Catalysts
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The selective hydrogenation of 9-aminoacridine (1) into 1,2,3,4-tetrahydro-derivative (2) was searched using noble metal catalysts (Pd, Rh, Pt, and Ru) at around 80 deg C and 60 atm of H2.The Pd/Al2O3 catalyst was found most selective to produce 2 in a higher yield of 60 percent at a conversion of 97 percent.The hydrogenation pathway of 1 is discussed in comparison with that of acridine.
- Sakanishi, Kinya,Mochida, Isao,Okazaki, Hiroshi,Soeda, Mahito
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p. 319 - 322
(2007/10/02)
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